[Left atrial appendage closure in non-valvular atrial fibrillation]. / Verschluss des linken Vorhofohrs bei nichtvalvulärem Vorhofflimmern.

Atrial fibrillation is the most frequent cardiac arrhythmia worldwide, causing approximately 20% of all ischemic strokes. Therefore, oral anticoagulation is recommended in patients with atrial fibrillation with at least a moderate risk of stroke; however, there is a significant proportion of patients who cannot undergo long-term oral anticoagulation. As the left atrial appendage is of major relevance for atrial fibrillation-induced thrombus formation, catheter-based or surgical closure of the left atrial appendage appears to be a promising therapeutic option. Large registry studies including patients with catheter-based left atrial appendage closure have proven its effectiveness and a decreasing procedure-related complication rate. This review article summarizes the current knowledge and introduces major ongoing randomized studies, which will investigate the impact of left atrial appendage closure on stroke prevention. The authors hope that the results of the randomized CLOSURE AF trial, which is funded by the German Center for Cardiovascular Research e. V. and is now recruiting patients in Germany, will help to solve many of the currently prevalent clinical questions.

Dual antiplatelet therapy after percutaneous coronary intervention for stable CAD or ACS : Redefining the optimal duration of treatment.

The duration and combination of dual antiplatelet therapy after coronary stent implantation, consisting of aspirin and a P2Y12 inhibitor, is among the most intensely investigated therapeutic strategies in cardiovascular medicine. While initial studies have mainly focused on the efficacy and safety of individual antithrombotic agents, the increased need for a personalized, risk-based approach to define the optimal duration of antithrombotic treatment according to the estimated ischemic and bleeding risk was then recognized. Recent recommendations for the optimal duration of antithrombotic combination therapies following coronary stent implantation in various clinical scenarios have substantially changed. The aim of the present article is to discuss the recent evidence from randomized clinical trials and observational studies with respect to antithrombotic treatment regimens in patients undergoing coronary artery stenting for stable coronary artery disease (CAD) or an acute coronary syndrome (ACS). We will focus on optimal treatment duration and a personalized approach based on ischemic and bleeding risk assessment.

[Catheter-based atrial appendage closure-current data and future developments]. / Der katheterbasierte Vorhofohrverschluss ­ aktuelle Daten und künftige Entwicklungen.

In Germany more than 1.6 million patients suffer from atrial fibrillation (AF). Within the next decades this number will substantially increase due to current demographic trends with the increasing average age of the population. When untreated, patients with atrial fibrillation have a five times higher risk for stroke as compared with a control cohort. A potent stroke prevention therapy reducing the risk of stroke by approximately 70-80% is primarily treatment with new oral anticoagulants (NOACs). The risk scores for stroke (CHA2DS2-VASc) and major bleeding (HAS-BLED) in patients with atrial fibrillation share common variables, so that patients with the highest stroke risk often carry a very high bleeding risk. A significant number of patients (ca. 20-30%) are, however, not eligible for long-term anticoagulation, e.g. because of a high bleeding risk. For this population there is an urgent need for alternative stroke prevention strategies, such as catheter-based percutaneous left atrial appendage closure. Current data about the efficiency and safety of this treatment as well as a discussion of ongoing recruitment for randomized studies are discussed in this review.

[Dyslipidemias : Diagnostics and management]. / Fettstoffwechselstörungen : Diagnostik und Therapie.

For disorders of lipid metabolism the risk-adapted adjustment of low-density lipoprotein (LDL) cholesterol remains the primary treatment target, as a causal role in minimizing the progression of ACVD has been shown. Because of their efficacy in reducing cardiovascular morbidity and mortality, statins are recommended as first-line pharmacological treatment in dyslipidemias. Additionally, ezetimibe and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition have been shown to significantly reduce cardiovascular events in high-risk patients. Life style changes can improve the plasma lipid profile, particularly in the setting of hypertriglyceridemia. Evaluation of high-density lipoprotein (HDL) cholesterol and lipoprotein(a) provides further information when assessing the individual cardiovascular risk, but direct evidence that pharmacologically targeting HDL cholesterol or Lp(a) results in a reduction of cardiovascular events has not yet been shown.

[Clinical importance of HDL cholesterol]. / Klinische Bedeutung des HDL-Cholesterins.

BACKROUND: Each year 16-17 million determinations of high-density lipoprotein cholesterol (HDL-C) are conducted and interpreted in Germany. Recently acquired data have led to a fundamental reassessment of the clinical significance of HDL-C. METHOD: This review article is based on a selective literature search. RESULTS: Low HDL­C levels usually indicate an increased cardiovascular risk, particularly in primary prevention but the epidemiological relationship between HDL­C and the risk is complex. The HDL plays a role in the back transport and excretion of cholesterol; however, the biological functions of HDL are dependent on the protein and lipid composition, which is not reflected by the HDL­C concentration. If the composition of HDL is pathologically altered it can also exert negative vascular effects. CONCLUSION: Compared with low-density lipoprotein cholesterol (LDL-C), HDL­C is of secondary importance for cardiovascular risk stratification and the calculation of the LDL-C:HDL­C ratio is not useful for all patients. Low HDL­C levels should prompt a search for additional metabolic and inflammatory pathologies. An increase in HDL­C through lifestyle changes (e.g. smoking cessation and physical exercise) has positive effects and is recommended; however, HDL­C is currently not a valid target for drug therapy.

[ECS guidelines 2016 - dyslipidaemias]. / ESC-Leitlinien 2016 ­ Dyslipidämien.

Dyslipidaemia is a major cause of atherosclerotic cardiovascular disease and its progression towards clinical complications, such as acute coronary syndromes and stroke. In August 2016 the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS) issued new joint guidelines for the management of dyslipidaemias. In these new guidelines, the concept of treating patients to a risk-based low-density lipoprotein (LDL) cholesterol target is reinforced. The task force considers LDL cholesterol as the primary target for dyslipidaemia treatment, whereas high-density lipoprotein (HDL) cholesterol is not recommended as a treatment target (based on the failure of HDL cholesterol elevation treatment strategies to reduce cardiovascular risk in recent studies). In patients with a very high risk for cardiovascular events it is recommended to treat to an LDL cholesterol target of less than 70 mg/dl. Moreover, the new guidelines now additionally recommend a > 50% reduction of LDL cholesterol in patients with very high cardiovascular risk patients and baseline levels between 70 and 135 mg/dl as well as in patients with high cardiovascular risk and baseline LDL cholesterol levels between 100 and 200 mg/dl. Statins are recommended as first-line medicinal treatment and the LDL cholesterol goals given imply the more frequent use of maximum tolerated statin therapy, in particular for patients with very high cardiovascular risk. Treatment with ezetimibe in patients with substantially elevated LDL cholesterol levels despite maximum tolerated statin therapy has now received a stronger recommendation (currently IIa recommendation). The guidelines also now include the potential use of the novel proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors and a recent ESC/EAS consensus document provides more detailed information on which patients can be considered for treatment with PCSK9 inhibitors, i. e. in particular patients with familial hypercholesterolemia and patients at very high cardiovascular risk who have markedly elevated LDL cholesterol levels despite maximum tolerated statin and ezetimibe therapy.

[Impact of lipid metabolism parameters on the development and progression of coronary artery disease : An update]. / Einfluss der Lipidstoffwechselparameter auf die Entstehung und Progression der koronaren Herzerkrankung : Ein Update.

Disorders of lipid metabolism play a major role in the development and progression of coronary artery disease. Dyslipidemia therefore plays a central role in therapeutic approaches for prevention and treatment of cardiovascular events associated with coronary artery disease. Epidemiological studies have shown an association between various lipid metabolism parameters, the risk of developing coronary artery disease and progression of a pre-existing disease. In particular, increased levels of low-density lipoprotein cholesterol (LDL-C), reduced levels of HDL cholesterol (HDL-C), as well as high levels of triglycerides and increased lipoprotein(a) [Lp(a)] levels can be taken into account when assessing the risk stratification of patients for primary prevention of coronary artery disease. Lifestyle and dietary changes, intensified statin therapy and possibly the addition of ezetimibe remain the major interventions in both primary and secondary prevention of coronary artery disease, as they improve the prognosis particularly by lowering levels of LDL-C. Recently, genetic studies have contributed to extending our understanding of the relationship between lipid metabolism and coronary artery disease. A causal role for progression of coronary artery disease could be demonstrated for LDL-C, Lpa and triglyceride-rich lipoproteins (TRL), which could not be demonstrated for HDL-C in various studies. Furthermore, the effect of reduction of LDL-C by proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition and by the cholesteryl ester transfer protein (CETP) inhibitor anacetrapib on cardiovascular events is currently being investigated in large clinical outcome study programs.

[Catheter-based closure of the left atrial appendage : Stroke prevention in atrial fibrillation]. / Der katheterbasierte Verschluss des linken Vorhofohrs : Schlaganfallprävention bei Vorhofflimmern.

In patients with nonvalvular atrial fibrillation, >90 % of thrombi are detected in the left atrial appendage (LAA). In particular these observations have resulted in the development of catheter-based LAA closure as an approach for stroke prevention in patients with nonvalvular atrial fibrillation in recent years. A preliminary randomized trial provided promising data with respect to efficacy and safety of this approach as compared to anticoagulation with warfarin. The safety of the procedure has been significantly improved in recent years due to procedural experience and refinement of implanted devices. In current clinical practice, this approach is particularly used for patients with nonvalvular atrial fibrillation, a significant ischemic risk (CHA2DS2-VASc score ≥2), and a high bleeding risk, i. e., in patients in whom there are relevant concerns with respect to long-term anticoagulation. The present article discusses the data from randomized clinical studies and registries, the present guideline recommendations, and the practical clinical use of LAA closure for stroke prevention.

The Year in Cardiology 2013: cardiovascular disease prevention.

The decline in cardiovascular mortality in Europe by nearly 50% over the last three decades resulted in particular from improved risk factor control and prevention interventions in addition to improved treatment. This review provides an overview of key studies in epidemiology, hypertension control, lipidology, diabetology, and lifestyle changes published in 2013. EXAMINE in diabetology and AIM-High and HPS-2-THRIVE in lipidology failed to demonstrate an event reduction. According to EUROASPIRE IV clinical implementation of secondary prevention treatments is still suboptimal. The 2013 study highlights in prevention prove the dynamic progress of knowledge in the field;, however, knowledge alone is futile without implementation.

[New AHA and ACC guidelines on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk : Statement of the D•A•CH Society for Prevention of Cardiovascular Diseases, the Austrian Atherosclerosis Society and the Working Group on Lipids and Atherosclerosis (AGLA) of the Swiss Society for Cardiology]. / Neue AHA- und ACC-Leitlinie zur Risikoreduktion von Herz-Kreislauf-Erkrankungen durch Cholesterinsenkung : Stellungnahme der D•A•CH-Gesellschaft Prävention von Herz-Kreislauf-Erkrankungen e. V., der Österreichischen Atherosklerose Gesellschaft und der Arbeitsgruppe Lipide und Atherosklerose (AGLA) der Schweizer Gesellschaft für Kardiologie.

Guidelines for the reduction of cholesterol to prevent atherosclerotic vascular events were recently released by the American Heart Association and the American College of Cardiology. The authors claim to refer entirely to evidence from randomized controlled trials, thereby confining their guidelines to statins as the primary therapeutic option. The guidelines derived from these trials do not specify treatment goals, but refer to the percentage of cholesterol reduction by statin medication with low, moderate, and high intensity. However, these targets are just as little tested in randomized trials as are the cholesterol goals derived from clinical experience. The same applies to the guidelines of the four patient groups which are defined by vascular risk. No major statin trial has included patients on the basis of their global risk; thus the allocation criteria are also arbitrarily chosen. These would actually lead to a significant increase in the number of patients to be treated with high or maximum dosages of statins. Also, adhering to dosage regulations instead of cholesterol goals contradicts the principles of individualized patient care. The option of the new risk score to calculate lifetime risk up to the age of 80 years in addition to the 10-year risk can be appreciated. Unfortunately it is not considered in the therapeutic recommendations provided, despite evidence from population and genetic studies showing that even a moderate lifetime reduction of low-density lipoprotein (LDL) cholesterol or non-HDL cholesterol has a much stronger effect than an aggressive treatment at an advanced age. In respect to secondary prevention, the new American guidelines broadly match the European guidelines. Thus, the involved societies from Germany, Austria and Switzerland recommend continuing according to established standards, such as the EAS/ESC guidelines.

An unbalanced monocyte polarisation in peripheral blood and bone marrow of patients with type 2 diabetes has an impact on microangiopathy.

AIM/HYPOTHESIS: Monocytes/macrophages play important roles in adipose and vascular tissues and can be polarised as inflammatory M1 or anti-inflammatory M2. We sought to analyse monocyte polarisation status in type 2 diabetes, which is characterised by chronic inflammation. METHODS: We enrolled 60 individuals without diabetes and 53 patients with type 2 diabetes. We quantified standard monocyte subsets defined by cluster of differentiation (CD)14 and CD16. In addition, based on the phenotype of polarised macrophages in vitro, we characterised and quantified more definite M1 (CD68(+)CCR2(+)) and M2 (CX3CR1(+)CD206(+)/CD163(+)) monocytes. We also analysed bone marrow (BM) samples and the effects of granulocyte-colony stimulating factor (G-CSF) stimulation in diabetic and control individuals. RESULTS: We found no alterations in standard monocyte subsets (classical, intermediate and non-classical) when comparing groups. For validation of M1 and M2 phenotypes, we observed that M2 were enriched in non-classical monocytes and had lower TNF-α content, higher LDL scavenging and lower transendothelial migratory capacity than M1. Diabetic patients displayed an imbalanced M1/M2 ratio compared with the control group, attributable to a reduction in M2. The M1/M2 ratio was directly correlated with waist circumference and HbA1c and, among diabetic patients, M2 reduction and M1/M2 increase were associated with microangiopathy. A decrease in M2 was also found in the BM from diabetic patients, with a relative M2 excess compared with the bloodstream. BM stimulation with G-CSF mobilised M2 macrophages in diabetic but not in healthy individuals. CONCLUSIONS/INTERPRETATION: We show that type 2 diabetes markedly reduces anti-inflammatory M2 monocytes through a dysregulation in bone-marrow function. This defect may have a negative impact on microangiopathy.

Magnetocardiography at rest predicts cardiac death in patients with acute chest pain.

Introduction: Sudden cardiac arrest is a major cause of morbidity and mortality worldwide and remains a major public health problem for which better non-invasive prediction tools are needed. Primary preventive therapies, such as implantable cardioverter defibrillators, are not personalized and not predictive. Most of these devices do not deliver life-saving therapy during their lifetime. The individual relationship between fatal arrhythmias and cardiac function abnormalities in predicting cardiac death risk has rarely been explored. Methods: We retrospectively analyzed the measurements at rest for 191 patients with acute chest pain (ACP) magnetocardiographically. Our recently introduced analyses are able to detect inhomogeneities of the depolarization and repolarization. Moreover, electrically silent phenomena-intracellular ionic currents as well as vortex currents-can be measured and quantified. All included ACP patients were recruited in 2009 at Yonsei University Hospital and were followed up until 2022. Results: During half of the follow-up period (6.5 years), 11 patients died. Out of all the included nine clinical, eight magnetocardiographical, and nine newly introduced magnetoionographical parameters we tested in this study, three parameters revealed themselves to be outstanding at predicting death: heart rate-corrected QT (QTc) prolongation, depression of repolarization current IKr + IKs, and serum creatinine (all significant in Cox regression, p < 0.05). They clearly predicted cardiac death over the 6.5 years duration (sensitivity 90.9%, specificity 85.6%, negative predictive accuracy 99.4%). Cardiac death risk was more than ninefold higher in patients with low repolarization reserve and QTc prolongation in comparison with the remaining patients with ACP (p < 0.001). The non-parametric Kaplan-Meier statistics estimated significantly lower survival functions from their lifetime data (p < 0.001). Discussion: To the best of our knowledge, these are the first data linking magnetocardiographical and magnetoionographical parameters and subsequent significant fatal events in people, suggesting structural and functional components to clinical life-threatening ventricular arrhythmogenesis. The findings support investigation of new prevention strategies and herald those new non-invasive techniques as complementary risk stratification tools.

Medical graphics to improve patient understanding and anxiety in elderly and cognitively impaired patients scheduled for transcatheter aortic valve implantation (TAVI).

BACKGROUND: Anxiety and limited patient comprehension may pose significant barriers when informing elderly patients about complex procedures such as transcatheter aortic valve implantation (TAVI). OBJECTIVES: We aimed to evaluate the utility of medical graphics to improve the patient informed consent (IC) before TAVI. METHODS: In this prospective, randomized dual center study, 301 patients were assigned to a patient brochure containing medical graphics (Comic group, n = 153) or sham information (Control group, n = 148) on top of usual IC. Primary outcomes were patient understanding of central IC-related aspects and periprocedural anxiety assessed by the validated Spielberger State Trait Anxiety Inventory (STAI), both analyzed by cognitive status according to the Montreal Cognitive Assessment (MoCA). RESULTS: Patient understanding was significantly higher in the Comic group [mean number of correct answers 12.8 (SD 1.2) vs. 11.3 (1.8); mean difference 1.5 (95% CI 1.2-1.8); p < 0.001]. This effect was more pronounced in the presence of cognitive dysfunction (MoCA < 26) [12.6 (1.2) in the Comic vs. 10.9 (1.6) in the Control group; mean difference 1.8 (1.4-2.2), p < 0.001]. Mean STAI score declined by 5.7 (95% CI 5.1-6.3; p < 0.001) in the Comic and 0.8 points (0.2-1.4; p = 0.015) in the Control group. Finally, mean STAI score decreased in the Comic group by 4.7 (3.8-5.6) in cognitively impaired patients and by 6.6 (95% CI 5.8 to 7.5) in patients with normal cognitive function (p < 0.001 each). CONCLUSIONS: Our results prove beneficial effects for using medical graphics to inform elderly patients about TAVI by improving patient understanding and reducing periprocedural anxiety (DRKS00021661; 23/Oct/2020). Medical graphics entailed significant beneficial effects on the primary endpoints, patient understanding and periprocedural anxiety, compared to the usual patient informed consent (IC) procedure. Patient understanding of IC-related aspects was significantly higher in the Comic group, with a more pronounced benefit in patients with cognitive impairment (p for IC method and cognitive status < 0.001, respectively; p for IC method x MoCA category interaction = 0.017). There further was a significant decline of periprocedural anxiety in patients with and without cognitive impairment (p for IC method x measuring time point < 0.001; p for IC method x MoCA category x measuring time point interaction = 0.018).

High interindividual variability in LDL-cholesterol reductions after inclisiran administration in a real-world multicenter setting in Germany.

BACKGROUND AND AIMS: Low-density lipoprotein cholesterol (LDL-C) is the main therapeutic target in the treatment of hypercholesterolemia. Small interfering RNA (siRNA) inclisiran is a new drug, which targets PCSK9 mRNA in the liver, reducing concentrations of circulating LDL-C. In randomized trials, inclisiran demonstrated a substantial reduction in LDL-C. The German Inclisiran Network (GIN) aims to evaluate LDL-C reductions in a real-world cohort of patients treated with inclisiran in Germany. METHODS: Patients who received inclisiran in 14 lipid clinics in Germany for elevated LDL-C levels between February 2021 and July 2022 were included in this analysis. We described baseline characteristics, individual LDL-C changes (%) and side effects in 153 patients 3 months (n = 153) and 9 months (n = 79) after inclisiran administration. RESULTS: Since all patients were referred to specialized lipid clinics, only one-third were on statin therapy due to statin intolerance. The median LDL-C reduction was 35.5% at 3 months and 26.5% at 9 months. In patients previously treated with PCSK9 antibody (PCSK9-mAb), LDL-C reductions were less effective than in PCSK9-mAb-naïve patients (23.6% vs. 41.1% at 3 months). Concomitant statin treatment was associated with more effective LDL-C lowering. There was a high interindividual variability in LDL-C changes from baseline. Altogether, inclisiran was well-tolerated, and side effects were rare (5.9%). CONCLUSION: In this real-world patient population referred to German lipid clinics for elevated LDL-C levels, inclisiran demonstrated a high interindividual variability in LDL-C reductions. Further research is warranted to elucidate reasons for the interindividual variability in drug efficacy.

Results from a real-time dosimetry study during left atrial ablations performed with ultra-low dose radiation settings.

BACKGROUND: Three-dimensional mapping systems and the use of ultra-low dose radiation protocols have supported minimization of radiation dose during left atrial ablation procedures. By using optimal shielding, scattered radiation reaching the operator can be further reduced. This prospective study was designed to determine the remaining operator radiation exposure during left atrial catheter ablations using real-time dosimetry. METHODS: Radiation dose was recorded using real-time digital dosimetry badges outside the lead apron during 201 consecutive left atrial fibrillation ablation procedures. All procedures were performed using the same X­ray system (Siemens Healthineers Artis dBc; Siemens Healthcare AG, Erlangen, Germany) programmed with ultra-low dose radiation settings including a low frame rate (two frames per second), maximum copper filtration, and an optimized detector dose. To reduce scattered radiation to the operators, table-suspended lead curtains, ceiling-suspended leaded plastic shields, and radiation-absorbing shields on the patient were positioned in an overlapping configuration. RESULTS: The 201 procedures included 139 (69%) pulmonary vein isolations (PVI) (20 cryoballoon ablations, 119 radiofrequency ablations, with 35 cases receiving additional ablation of the cavotricuspid isthmus) and 62 (31%) PVI plus further left atrial substrate ablation. Mean radiation dose measured as dose area product for all procedures was 128.09 ± 187.87 cGy ∙ cm2 with a mean fluoroscopy duration of 9.4 ± 8.7 min. Real-time dosimetry showed very low average operator doses of 0.52 ± 0.10 µSv. A subanalysis of 51 (25%) procedures showed that the radiation burden for the operator was highest during pulmonary vein angiography. CONCLUSION: The use of ultra-low dose radiation protocols in combination with optimized shielding results in extremely low scattered radiation reaching the operator.

[Stem and progenitor cell-based therapy approaches: current developments on treatment of acute myocardial infarction and chronic ischemic cardiomyopathy]. / Stamm- und progenitorzellbasierte Therapieansätze : Aktuelle Entwicklungen zur Behandlung des akuten Myokardinfarkts und der chronischen ischämischen Kardiomyopathie.

Percutaneous coronary intervention (PCI) for coronary revascularization in conjunction with an optimized pharmacological treatment can reduce adverse left ventricular remodeling and dysfunction in patients with acute myocardial infarction. Despite these modern therapeutic strategies a significant number of these patients continue to develop adverse cardiac remodeling and LV dysfunction which is associated with a poor prognosis. Stem and progenitor cell-based approaches for treatment of acute myocardial infarction and chronic ischemic cardiomyopathy are an interesting direction of current experimental and clinical research. The current review article provides a summary of recent developments of cell-based therapies of ischemic heart disease, including the assessment of the repair and regeneration capacity of different stem and progenitor cell populations. In addition the advantages and disadvantages of different modes of cell application and potential strategies for the improvement of stem and progenitor cell function for their use in cell-based cardiovascular therapies will be described.

[Left atrial appendage occlusion in patients with nonvalvular atrial fibrillation : Present evidence, ongoing studies, open questions]. / Verschluss des linken Vorhofohrs bei nichtvalvulärem Vorhofflimmern : Datenlage, aktuelle Studien, offene Fragen.

About every fifth ischemic stroke is caused by atrial fibrillation. Oral anticoagulation is highly effective in secondary stroke prevention, but a relevant portion of patients with atrial fibrillation is not (permanently) anticoagulated for a variety of reasons. Based on present evidence, no general recommendation can be given for left atrial appendage occlusion in patients with nonvalvular atrial fibrillation. However, left atrial appendage occlusion is a treatment option after severe anticoagulation-related bleeding, if the cause of bleeding is not treatable. Left atrial appendage occlusion is critical in patients with a relative contraindication for oral anticoagulation or lack of adherence to given medication. It seems to be important that further randomized studies confirm a benefit of left atrial appendage occlusion in selected patients with nonvalvular atrial fibrillation. In addition, it is vital to clarify whether discontinuation of antiplatelets is feasible after catheter-based left atrial appendage occlusion, as antiplatelets are associated with a risk of bleeding. Within this review article, we discuss present evidence, gaps of knowledge and provide an overview on ongoing clinical studies. In addition, we summarize the design of the CLOSURE-AF study. This randomized multicenter study will start recruitment soon and is funded by the German Center for Cardiovascular Research e. V.